This case is related to Merck case U.S. Pat. No. 5,413,999.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci. 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature 329, 351 (1987)].
The compound L-735,524 is a potent inhibitor of HIV protease and is useful in the treatment of AIDS or ARC, without substantial side effects or toxicity.
Applicants have discovered that administration of L-735,524 may require dosing as frequently as every four hours. To solve this problem, a combination therapy for AIDS has been discovered by applicants.
Applicants demonstrate that the combination of compounds of this invention is an effective inhibitor of HIV protease.
In the present invention, applicants co-administer a potent HIV protease inhibitor, such as L-735,524 or other chemical entities, with ketoconazole or cimetidine. This combination therapy is a method to enhance the pharmacokinetics of the HIV protease inhibitor which may have a short serum half-life due to rapid metabolism by P.sub.450 isozymes. Cimetidine and ketoconazole are inhibitors of P.sub.450 isozymes.